US5280030A - Piperidine derivatives, their preparation and their therapeutic application - Google Patents
Piperidine derivatives, their preparation and their therapeutic application Download PDFInfo
- Publication number
- US5280030A US5280030A US07/862,376 US86237692A US5280030A US 5280030 A US5280030 A US 5280030A US 86237692 A US86237692 A US 86237692A US 5280030 A US5280030 A US 5280030A
- Authority
- US
- United States
- Prior art keywords
- sub
- compound
- group
- pyridin
- atom
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present invention relates to piperidine derivatives, their preparation and their therapeutic application.
- the present invention provides a compound which is a piperidine derivative of general formula (I) ##STR2## in which R 1 represents a hydrogen atom, a linear or branched (C 1-6 )alkyl group or a cyclo(C 3-8 )alkyl group, X represents an oxygen atom, a sulphur atom or a group of general formula N-R 3 in which R 3 is a hydrogen atom, or a linear or branched (C 1-8 )alkyl, cyclo(C 3-6 )alkyl, cyclo(C 3-6 )alkylmethyl, (C 1-4 )alkoxy-(C 1-4 )alkyl, phenyl, pyridin-4-yl, pyridin-3-yl, pyridin-4-ylmethyl or pyridin-3-ylmethyl group and Z represents a hydrogen or fluorine atom and acid addition salts thereof with pharmaceutically acceptable acids.
- R 1 represents a hydrogen atom, a
- the present invention also provides a process for the preparation of compounds of the invention.
- Preferred compounds of the present invention are compounds in which R 1 represents a hydrogen atom or a methyl or cyclohexyl group, X represents an oxygen atom, a sulphur atom or a group of general formula N--R 3 in which R 3 is a hydrogen atom, or a linear or branched (C 1-8 )alkyl, cyclopropyl, cyclo(C 3-6 )alkylmethyl, methoxyethyl, phenyl, pyridin-4-ylmethyl or pyridin-3-ylmethyl group and Z represents a hydrogen or fluorine atom.
- More preferred compounds according to the invention are the compounds in which
- R 1 represents a hydrogen atom or a linear or branched (C 1-6 )alkyl group
- X represents a group of general formula N--R 3 in which R 3 is a linear or branched (C 1-8 )alkyl group,
- Z represents a hydrogen atom.
- the preferred compounds are those in which R 1 represents with a hydrogen atom or a methyl group, X represents a (1-methylethyl)imino group, and Z represents a hydrogen atom.
- the compounds of the invention may exist as free bases or addition salts with pharmaceutically acceptable acids.
- reaction of the pyridine derivative of the general formula (IX) with hydroxylamine hydrochloride suitably takes place in the presence of concentrated sodium hydroxide in a solvent such as water.
- the compound of general formula (VIII) is reacted with tosyl chloride suitably in a solvent such as pyridine to obtain a compound of general formula (VII).
- This compound after reaction with potassium ethylate in absolute ethanol, reacts so as to give an unstable cyclic intermediate which is hydrolysed, using concentrated hydrochloric acid suitably in water to obtain a compound of general formula (VI).
- Suitable acid addition salts are the hydrochlorides, fumarates, maleates or oxalates.
- the starting compounds are described in the literature or they may be prepared according to methods which are described therein or which are known to a person skilled in the art.
- the compounds of general formula (IX) in which R 1 represents a hydrogen atom are commercially available. Those for which R 1 is other than a hydrogen atom are prepared from 4-cyanopyridine by the action of the corresponding organomagnesium compound R 1 -CH 2 -Mg-Hal where Hal is Br or Cl, followed by acid hydrolysis.
- Chlorine-containing derivatives of general formula (II) in which X represents an oxygen atom are described in J. Med. Chem., 1988, 31, 1719-28.
- N-phenyl group Those in whose formula X represents an N-phenyl group can be obtained from N-phenylbenzene-1,2-diamine, firstly by reaction with urea to form 1-phenylbenzimidazolone, and then by reaction with phosphoryl chloride.
- the aqueous phases are then combined and concentrated under vacuum at a temperature of not more than 40° C.
- the residue is taken up in an ethanol/toluene mixture in proportions of 50:50 v/v.
- the resulting suspension is evaporated under vacuum to remove traces of water.
- the crystallised residue is taken up in 50 ml of hot ethanol. This solution is cooled, filtered, washed with ethanol and then dried under vacuum over phosphorus pentoxide. 49 g of compound are obtained.
- the mixture is heated at 120° C. by means of an oil bath for 24 hours.
- the precipitate of excess (6 g) piperidine hydrochloride (1:1) is filtered.
- the filtrate is evaporated to dryness and the residue is purified on a silica gel column eluting with a mixture of dichloromethane and methanol in proportions of 90:10 v/v.
- the pure fractions are combined and evaporated.
- the solid is washed with acetone and then dried under vacuum. 9.5 g of compound are obtained.
- a solution of 139 g (2 moles) of bydroxylamine hydrochloride in 280 ml of water is added, in a round bottomed flask, to a solution of 200 ml (2 moles) of 10 N sodium hydroxide in 180 ml of water while maintaining the temperature at around -5° C.
- 200 g (1.65 moles) of 1-(pyridin-4-yl)ethanone are rapidly added and the stirring is continued for 2 hours at 0° C.
- the precipitate formed is filtered and washed several times with ice-cold water. It is recrystallised from 4 liters of hot water and the solution is allowed to cool overnight. The crystals are drained, washed with water and dried in an oven over phosphorus pentoxide. 148 g of compound are obtained.
- the organic filtrate is added slowly, and under an argon atmosphere, to a solution of 350 ml (2.1 moles) of 6 N hydrochloric acid in 800 ml of water.
- the mixture is decanted, the organic phase is washed again with 200 ml of 2 N hydrochloric acid, the aqueous phases are combined and concentrated under vacuum at a temperature of not more than 40° C.
- the crystallised residue is taken up in 200 ml of hot ethanol.
- the mixture is cooled, filtered, washed with ethanol and then the precipitate is dried under vacuum. 200 g of compound are obtained.
- a mixture of 200 g (0.956 mole) of the above compound, 92.8 g (0.956 mole) of potassium thiocyanate and 800 ml of water is heated at 110° C. by means of an oil bath for 1.5 hours. The mixture is allowed to cool to around 40° C., the precipitate formed is filtered and washed with water. 80 g (0.95 mole) of sodium bicarbonate in 500 ml of water are then added in small portions. The precipitate is filtered, washed with water and dried under vacuum. 66.5 g of compound are obtained.
- the filtrate is evaporated to dryness.
- the residue obtained is purified on a silica gel column eluting with a mixture of dichloromethane and methanol in proportions ranging from 95:5 to 90:10 v/v.
- the pure fractions are combined and evaporated.
- the solid is washed with ether and dried under vacuum. 14.3 g of compound are obtained.
- the compounds of the invention have been the subject of pharmacological trials which have shown their usefulness as therapeutically active substances.
- the membranes are recovered by filtration on Whatman GF/BTM filters pretreated with 0.05% of polyethylenimine, and they are washed with three volumes of 5 ml of 50 mM ice-Cold Tris-HCl buffer.
- the radioactivity retained on the filters is measured by liquid scintillation spectrometry at an efficiency of 50 to 60%.
- the results are expressed as the concentration (IC 50 ) of the test compound which inhibits 50% of the [ 3 H]quipazine binding, determined by a graphical or mathematical method.
- the compounds of the invention which are most active in this trial are characterised by IC 50 values of less than 1 nM (10 -9 M).
- the compounds of the invention were also tested with respect to their effect on the Bezold-Jarisch reflex, that is to say an intense bradycardia caused by intravenous injection of serotonin.
- This reflex calls into play the stimulation of 5-HT 3 -specific receptors of the vagus nerve, which causes a depolarisation and therefore a secretion of acetylcholine which is the natural vagal neurotransmitter.
- Male Sprague-Dawley rats are anaesthetised with urethane (1 to 25 g/kg via intraperitoneal administration), the blood pressure is measured by means of a catheter placed in the carotid artery, and pressure pulses are used to activate a cardiotachometer.
- Cannulas are inserted in the two femoral veins in order to facilitate the intravenous administration of the products.
- Dose/response curves are plotted for the bradycardia caused by the injection of doses of 30 ⁇ g/kg of serotonin before and after injection of the test compounds.
- the compounds of the invention which are most active in this trial inhibit the serotonin-induced bradycardia by at least 50% at an intravenously administered dose of 10 ⁇ g/kg.
- Another in vivo test is that of the emptying of the stomach in rats, according to a procedure described by Scarpignato (J. Pharmacol., (Paris) 14(2). 261-268, 1983).
- the animals are 180 to 200-g male CD rats that have been starved for 24 h.
- the test compounds are administered intraperitoneally or orally 15 or 30 min before absorbing an indigestable liquid meal (methylcellulose and phenol red).
- the animals are sacrificed 10 min after administering the meal and the amount of phenol red remaining in the stomach is assayed by spectrophotometry, a group of control rats being sacrificed immediately after the meal.
- the compounds of the invention which are most active in this trial increase the emptying of the stomach after an intraperitoneally or orally administered dose of 1 mg/kg.
- the compounds of the invention were also studied with respect to their effects on emesis in ferrets (male, 1 to 1.4 kg), according to a method described by Costall et al., (Neuropharmacology 25(8), 959-961, 1986).
- the test compounds or saline are administered intravenously (jugular vein), under halothane anaesthesia, immediately before an intravenous infusion of cisplatin (10 mg/kg in 10 min).
- the animals are then observed for 3 h, noting the number of emetic episodes, the total number of spasms and vomiting as well as the time taken before the appearance of the first attack.
- the compounds of the invention which are most active in this trial show an antiemetic effect after intravenous administration of a dose of less than 5 mg/kg.
- the ileum is mounted on a 2-ml pipette and the longitudinal muscle is carefully separated with dental cotton wool impregnated with Krebs buffer.
- the organ is connected to an isometric transducer at a basal tension of 0.5 g and maintained in a Krebs bath at 37° C. which is aerated with a carbogen stream.
- an electric stimulation is applied (0.2 Hz; 1.5 ms; supramaximal voltage ⁇ 45 V) by means of H. Sachs model F2H field electrodes linked to a Grass S88TM stimulator until the contractions (or “twitches") are stabilised.
- 3 ⁇ 10 -7 phenoxybenzamine is then added to the bath, which reduces the amplitude of the contractions up to about 50% ( ⁇ 30 min).
- the organ is then washed six times at 5 min intervals. Serotonin (3 ⁇ 10-7 M) is added before the fourth wash. If necessary, the amplitude of the contractions is reduced to 50% of the supramaximal amplitude by reducing the electric voltage after the sixth wash.
- a graph of concentration effect by cumulative additions, at 1 min intervals, of the test compound is plotted.
- the responses are measured in terms of the capacity to restore the amplitude of the contractions to the level of that obtained by means of the supra-maximal voltage and after treatment with phenoxybenzamine.
- the compounds of the invention behave like agonists, partial agonists or antagonists of the said receptors, some of them being active at concentrations of less than 10 nM.
- the compounds of the invention are serotoninergic receptor ligands. As shown above, they interact in particular with the 5-HT 3 and 5-HT 4 -type receptors. They can therefore be used in the treatment and prevention of disorders in which 5-HT receptors are involved, such as nausea and vomiting, for example resulting from an antitumour treatment or from the administration of an anaesthetic; disorders of the central nervous system such as schizophrenia; mania, anxiety and depression; cognition disorders such as Alzheimer's senile or presenile dementia; dyskinesia, pain, migraine and headaches; disorders resulting from dependency on or withdrawal from alcohol or drugs; disorders of the gastrointestinal function such as dyspepsia, peptic ulcer, pyrosis, flatulence; disorders of the cardiovascular system and respiratory disorders.
- disorders of the central nervous system such as schizophrenia; mania, anxiety and depression
- cognition disorders such as Alzheimer's senile or presenile dementia
- dyskinesia pain, migraine and headaches
- disorders resulting from dependency on or withdrawal from alcohol or drugs
- they may be provided in any form suitable for oral or parenteral administration, such as tablets, sugared pills, hard gelatin capsules, capsules, suspensions or solutions taken orally or injected and the like, in combination with appropriate excipients, and in doses which permit administration of 0.005 to 5 mg/kg, 1 to 4 times daily.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9104009 | 1991-04-03 | ||
FR9104009A FR2674855B1 (fr) | 1991-04-03 | 1991-04-03 | Derives de piperidine, leur preparation et leur application en therapeutique. |
Publications (1)
Publication Number | Publication Date |
---|---|
US5280030A true US5280030A (en) | 1994-01-18 |
Family
ID=9411394
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US07/862,376 Expired - Fee Related US5280030A (en) | 1991-04-03 | 1992-04-02 | Piperidine derivatives, their preparation and their therapeutic application |
Country Status (19)
Country | Link |
---|---|
US (1) | US5280030A (ja) |
EP (1) | EP0507650B1 (ja) |
JP (1) | JPH0788378B2 (ja) |
KR (1) | KR920019778A (ja) |
CN (1) | CN1065459A (ja) |
AT (1) | ATE138375T1 (ja) |
AU (1) | AU646332B2 (ja) |
CA (1) | CA2064924A1 (ja) |
CS (1) | CS100192A3 (ja) |
DE (1) | DE69210875T2 (ja) |
FI (1) | FI921459A (ja) |
FR (1) | FR2674855B1 (ja) |
HU (1) | HUT62573A (ja) |
IE (1) | IE921048A1 (ja) |
IL (1) | IL101472A0 (ja) |
MX (1) | MX9201507A (ja) |
NO (1) | NO921281L (ja) |
NZ (1) | NZ242214A (ja) |
PL (1) | PL294088A1 (ja) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5418241A (en) * | 1992-09-28 | 1995-05-23 | Synthelabo | Piperidine derivatives, their preparation and their application in therapeutics |
US5589476A (en) * | 1993-10-04 | 1996-12-31 | Synthelabo | Imidazol-4-ylpiperidine derivatives, their preparation and their application in therapeutics |
US6096763A (en) * | 1995-02-23 | 2000-08-01 | Merck & Co., Inc. | α1a adrenergic receptor antagonists |
US20030119754A1 (en) * | 2001-05-11 | 2003-06-26 | Lackey John William | Benzimidazole compounds and antiviral uses thereof |
US20040082635A1 (en) * | 2001-06-26 | 2004-04-29 | Hiromasa Hashimoto | Fused cyclic compounds and medicinal use thereof |
US20040097438A1 (en) * | 1999-12-27 | 2004-05-20 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
US6887870B1 (en) * | 1999-10-12 | 2005-05-03 | Bristol-Myers Squibb Company | Heterocyclic sodium/proton exchange inhibitors and method |
US20050187390A1 (en) * | 2003-08-01 | 2005-08-25 | Genelabs Technologies, Inc. | Bicyclic heteroaryl derivatives |
US20050197323A1 (en) * | 1999-08-04 | 2005-09-08 | Lothar Farber | Use of 5-HT3 receptor antagonists for the treatment of inflammations of the respiratory tract |
WO2006090224A1 (en) | 2005-02-25 | 2006-08-31 | Pfizer Japan Inc. | Benzisoxazole derivatives |
US20060211698A1 (en) * | 2005-01-14 | 2006-09-21 | Genelabs, Inc. | Bicyclic heteroaryl derivatives for treating viruses |
US7112600B1 (en) | 1999-12-27 | 2006-09-26 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
US20130090324A1 (en) * | 2010-06-11 | 2013-04-11 | John S. Debenham | Novel prolylcarboxypeptidase inhibitors |
RU2597766C2 (ru) * | 2011-03-23 | 2016-09-20 | Раквалиа Фарма Инк. | Агонист рецептора 5-нт4 в качестве прокинетического агента |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993014745A1 (en) * | 1992-01-23 | 1993-08-05 | Smithkline Beecham Plc | Use of 5-ht4 receptor antagonists as medicaments for treating migraine |
US5380858A (en) * | 1992-04-01 | 1995-01-10 | The University Of Toledo | Process for the preparation of intermediates useful for the synthesis of histamine receptor antagonists |
FR2731707B1 (fr) * | 1995-03-13 | 1997-04-30 | Synthelabo | Derives de benzimidazole, leur preparation et leur application en therapeutique |
FR2731708B1 (fr) * | 1995-03-13 | 1997-04-30 | Synthelabo | Derives de piperidine, leur procede de preparation et leur application en therapeutique |
FR2765221B1 (fr) * | 1997-06-25 | 1999-07-30 | Synthelabo | Derives de 4-[(1h-imidazol-4-yl)piperidin-1-yl]anilide, leur preparation et leur application en therapeutique |
FR2765580B1 (fr) * | 1997-07-01 | 1999-08-06 | Synthelabo | Derives de (1h-imidazol-4-yl)piperidine, leur preparation et leur application en therapeutique |
FR2772377B1 (fr) * | 1997-12-12 | 2000-01-07 | Synthelabo | Derives de 1-(1-h-imidazol-2-yl)pyrrolidines et 1-(1-h-imidazol-2-ylpiperidines), leur preparation et leur application en therapeutique |
AU2002346216B2 (en) * | 1999-12-27 | 2005-12-08 | Japan Tobacco Inc. | Fused cyclic compounds and medicinal use thereof |
WO2014017938A2 (en) * | 2012-07-27 | 2014-01-30 | BIAL - PORTELA & Cª, S.A. | Process for the synthesis of substituted urea compounds |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0197840A1 (fr) * | 1985-03-26 | 1986-10-15 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | (Imidazolyl-4) piperidines, leur préparation et leur application en thérapeutique |
US4634704A (en) * | 1983-10-06 | 1987-01-06 | Janssen Pharmaceutica, N.V. | Anti-allergic five membered heterocyclic ring containing N-(bicyclic heterocycyl)-4-piperidinamines |
US4879301A (en) * | 1987-04-28 | 1989-11-07 | Hoei Pharmaceutical Co., Ltd. | Antiallergic and antiinflammatory benzothiazolinone derivatives |
EP0445026A1 (fr) * | 1990-02-27 | 1991-09-04 | Adir Et Compagnie | Dérivés d'aminométhyl-pipéridine, leur procÀ©dé de préparation et les compositions pharmaceutiques qui les contiennent |
-
1991
- 1991-04-03 FR FR9104009A patent/FR2674855B1/fr not_active Expired - Fee Related
-
1992
- 1992-03-23 EP EP92400780A patent/EP0507650B1/fr not_active Expired - Lifetime
- 1992-03-23 DE DE69210875T patent/DE69210875T2/de not_active Expired - Fee Related
- 1992-03-23 AT AT92400780T patent/ATE138375T1/de active
- 1992-04-02 FI FI921459A patent/FI921459A/fi not_active Application Discontinuation
- 1992-04-02 PL PL29408892A patent/PL294088A1/xx unknown
- 1992-04-02 HU HU9201116A patent/HUT62573A/hu unknown
- 1992-04-02 NO NO92921281A patent/NO921281L/no unknown
- 1992-04-02 JP JP4080690A patent/JPH0788378B2/ja not_active Expired - Lifetime
- 1992-04-02 KR KR1019920005518A patent/KR920019778A/ko not_active Application Discontinuation
- 1992-04-02 AU AU13989/92A patent/AU646332B2/en not_active Ceased
- 1992-04-02 CS CS921001A patent/CS100192A3/cs unknown
- 1992-04-02 CN CN92102327A patent/CN1065459A/zh active Pending
- 1992-04-02 IL IL101472A patent/IL101472A0/xx unknown
- 1992-04-02 IE IE104892A patent/IE921048A1/en unknown
- 1992-04-02 MX MX9201507A patent/MX9201507A/es unknown
- 1992-04-02 US US07/862,376 patent/US5280030A/en not_active Expired - Fee Related
- 1992-04-02 CA CA002064924A patent/CA2064924A1/en not_active Abandoned
- 1992-04-02 NZ NZ242214A patent/NZ242214A/xx unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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US4634704A (en) * | 1983-10-06 | 1987-01-06 | Janssen Pharmaceutica, N.V. | Anti-allergic five membered heterocyclic ring containing N-(bicyclic heterocycyl)-4-piperidinamines |
EP0197840A1 (fr) * | 1985-03-26 | 1986-10-15 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | (Imidazolyl-4) piperidines, leur préparation et leur application en thérapeutique |
US4879301A (en) * | 1987-04-28 | 1989-11-07 | Hoei Pharmaceutical Co., Ltd. | Antiallergic and antiinflammatory benzothiazolinone derivatives |
EP0445026A1 (fr) * | 1990-02-27 | 1991-09-04 | Adir Et Compagnie | Dérivés d'aminométhyl-pipéridine, leur procÀ©dé de préparation et les compositions pharmaceutiques qui les contiennent |
Non-Patent Citations (7)
Title |
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Barchas et al "Serotonin and Behavior" Academic Press, pp. 235-238 (1973). |
Barchas et al Serotonin and Behavior Academic Press, pp. 235 238 (1973). * |
Foks et al Pyraziue Derivatives CA 90:168536m (1979). * |
Glennon "Central Serotonin Receptors . . . " J. Med. Chem. 30(1) 1-12 (1986). |
Glennon Central Serotonin Receptors . . . J. Med. Chem. 30(1) 1 12 (1986). * |
Tyers et al "5-HT3 Receptors" N.Y. Academy Sci. 600 pp. 194-199, 215-216 (1990). |
Tyers et al 5 HT 3 Receptors N.Y. Academy Sci. 600 pp. 194 199, 215 216 (1990). * |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5418241A (en) * | 1992-09-28 | 1995-05-23 | Synthelabo | Piperidine derivatives, their preparation and their application in therapeutics |
US5589476A (en) * | 1993-10-04 | 1996-12-31 | Synthelabo | Imidazol-4-ylpiperidine derivatives, their preparation and their application in therapeutics |
US6096763A (en) * | 1995-02-23 | 2000-08-01 | Merck & Co., Inc. | α1a adrenergic receptor antagonists |
US20050197323A1 (en) * | 1999-08-04 | 2005-09-08 | Lothar Farber | Use of 5-HT3 receptor antagonists for the treatment of inflammations of the respiratory tract |
US6887870B1 (en) * | 1999-10-12 | 2005-05-03 | Bristol-Myers Squibb Company | Heterocyclic sodium/proton exchange inhibitors and method |
US6770666B2 (en) | 1999-12-27 | 2004-08-03 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
US7112600B1 (en) | 1999-12-27 | 2006-09-26 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
US20040097438A1 (en) * | 1999-12-27 | 2004-05-20 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
US7285551B2 (en) | 1999-12-27 | 2007-10-23 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
US20070032497A1 (en) * | 1999-12-27 | 2007-02-08 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
US20030119754A1 (en) * | 2001-05-11 | 2003-06-26 | Lackey John William | Benzimidazole compounds and antiviral uses thereof |
US7030150B2 (en) * | 2001-05-11 | 2006-04-18 | Trimeris, Inc. | Benzimidazole compounds and antiviral uses thereof |
US20060142365A1 (en) * | 2001-05-11 | 2006-06-29 | Trimeris, Inc. | Benzimidazole compounds and antiviral uses thereof |
US20040082635A1 (en) * | 2001-06-26 | 2004-04-29 | Hiromasa Hashimoto | Fused cyclic compounds and medicinal use thereof |
US7511145B2 (en) | 2003-08-01 | 2009-03-31 | Genelabs Technologies, Inc. | Bicyclic heteroaryl derivatives |
US20090081165A1 (en) * | 2003-08-01 | 2009-03-26 | Genelabs Technologies, Inc. | Bicyclic heteroaryl derivatives |
US20050187390A1 (en) * | 2003-08-01 | 2005-08-25 | Genelabs Technologies, Inc. | Bicyclic heteroaryl derivatives |
US20060211698A1 (en) * | 2005-01-14 | 2006-09-21 | Genelabs, Inc. | Bicyclic heteroaryl derivatives for treating viruses |
WO2006090224A1 (en) | 2005-02-25 | 2006-08-31 | Pfizer Japan Inc. | Benzisoxazole derivatives |
US8816090B2 (en) | 2005-02-25 | 2014-08-26 | Pfizer Inc. | Benzisoxazole derivatives |
US20130090324A1 (en) * | 2010-06-11 | 2013-04-11 | John S. Debenham | Novel prolylcarboxypeptidase inhibitors |
US9006268B2 (en) * | 2010-06-11 | 2015-04-14 | Merck Sharp & Dohme Corp. | Prolylcarboxypeptidase inhibitors |
RU2597766C2 (ru) * | 2011-03-23 | 2016-09-20 | Раквалиа Фарма Инк. | Агонист рецептора 5-нт4 в качестве прокинетического агента |
US10137113B2 (en) | 2011-03-23 | 2018-11-27 | Raqualia Pharma Inc. | 5-HT4 receptor agonist as a prokinetic agent |
Also Published As
Publication number | Publication date |
---|---|
CN1065459A (zh) | 1992-10-21 |
DE69210875D1 (de) | 1996-06-27 |
JPH05112563A (ja) | 1993-05-07 |
IL101472A0 (en) | 1992-12-30 |
FI921459A0 (fi) | 1992-04-02 |
JPH0788378B2 (ja) | 1995-09-27 |
NO921281L (no) | 1992-10-05 |
FR2674855B1 (fr) | 1994-01-14 |
CS100192A3 (en) | 1992-10-14 |
FI921459A (fi) | 1992-10-04 |
HU9201116D0 (en) | 1992-06-29 |
MX9201507A (es) | 1992-10-01 |
EP0507650A1 (fr) | 1992-10-07 |
PL294088A1 (ja) | 1993-02-08 |
HUT62573A (en) | 1993-05-28 |
CA2064924A1 (en) | 1992-10-04 |
EP0507650B1 (fr) | 1996-05-22 |
DE69210875T2 (de) | 1996-12-05 |
NZ242214A (en) | 1993-05-26 |
NO921281D0 (no) | 1992-04-02 |
FR2674855A1 (fr) | 1992-10-09 |
AU1398992A (en) | 1992-10-08 |
IE921048A1 (en) | 1992-10-07 |
KR920019778A (ko) | 1992-11-20 |
AU646332B2 (en) | 1994-02-17 |
ATE138375T1 (de) | 1996-06-15 |
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